Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Benzisoquinolinedione (nafidimide; NSC 308847) is an investigational drug currently in phase I clinical testing. We have studied the antileukemic activity in vitro, the cellular drug transport, and the molecular mechanism of action with DNA of this new compound. By agarose gel electrophoresis, we verified that nafidimide is an intercalating agent, through its alteration of the electrophoretic migration of DNA products produced by the relaxing action of DNA topoisomerase I. Concentrations of up to 100 microM of nafidimide did not produce topoisomerase I-mediated DNA cleavage. Nafidimide produced DNA single-strand breaks (SSB), double-strand breaks, and DNA-protein cross-links in human myeloid leukemia cells (measured with filter elution). The ratio of SSB/DNA-protein cross-links was 1.32 +/- 0.36, a value similar to that produced by 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA), suggesting that nafidimide, like m-AMSA, produced protein-associated DNA-strand breaks through a topoisomerase II-mediated reaction. The production of double-strand breaks by nafidimide also suggests the involvement of topoisomerase II in the drug-induced DNA cleavage. The cytotoxic activity of nafidimide was quantified in human myeloid leukemia cell lines differing by a factor of 70 in their cytotoxic sensitivity to m-AMSA. The m-AMSA-resistant line was less than 2-fold resistant to nafidimide. Cellular drug uptake was rapid and reached a steady state level in 30 min at 37 degrees C. At the end of exposure, drug egress was rapid, as was the disappearance of the DNA SSB. Rapid cellular uptake of nafidimide, with low retention at the end of exposure and rapid rejoining of DNA SSB suggest that prolonged cellular exposure may be necessary for optimal antitumor effect. In vitro cloning data suggest that nafidimide may be a therapeutic option for patients with leukemia resistant to m-AMSA.
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PMID:In vitro toxicity and DNA cleaving capacity of benzisoquinolinedione (nafidimide; NSC 308847) in human leukemia. 302 21

Sensitive (P388/S) and amsacrine-resistant (P388/amsacrine) sublines of P388 leukemia were cloned in vitro and tested for differential chemosensitivity against a panel of drugs. P388/amsacrine, resistant both in vivo and in vitro to amsacrine, was cross-resistant to other putative topoisomerase II inhibitors including teniposide, etoposide, bisantrene, and doxorubicin. P388/amsacrine, was however, as sensitive as cloned P388/S to camptothecin, an inhibitor of topoisomerase I. The pattern of cross-resistance suggested that an alteration in topoisomerase II may be involved in the resistance of P388/amsacrine to these drugs. No differences in the uptake of amsacrine were detected between the two sublines. Cross-resistance to vinblastine was evident in P388/amsacrine; however resistance to vinblastine was associated with alterations in uptake or efflux of the drug. The number of protein-concealed single-strand breaks induced in whole cells by amsacrine, teniposide, bisantrene, and camptothecin was measured. Diminished numbers of strand breaks in the resistant subline were consistent with decreases in DNA-protein crosslinks. In the absence of drug treatment, resistant cells sustained approximately one-half as many single-strand breaks and DNA-protein crosslinks as the sensitive cells during preparation of nuclei. As measured by the P4 phage DNA unknotting assay, 0.35 M NaCl nuclear extracts from P388/S contained approximately 2.3-fold more topoisomerase II catalytic activity than did extracts from P388/amsacrine. The amount of protein that immunoreacted with a specific antibody to calf thymus topoisomerase II was also decreased in the resistant cells. These data suggest that alterations in topoisomerase II which lead to differential drug sensitivities are partially responsible for the resistance of P388/amsacrine to a specific group of drugs.
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PMID:Characterization of a subline of P388 leukemia resistant to amsacrine: evidence of altered topoisomerase II function. 303 2

Pretreatment (4h) of human HL 60 leukemia cells with the topoisomerase I-inhibitor camptothecin (7-28 x 10(-9) Mol/l, single dose) enhanced vitamin D3-responsive CD 14 expression (10(-11)-10(-8) Mol/l vitamin D3) up to twofold, as measured by fluorescence activated flow cytometry after 1-3 days. Camptothecin by itself caused marginal effects. Hybridization of total RNA with oligonucleotides (bases 1358-1333 of CD 14 sequence) showed increased steady state levels of the 1.75 kb CD 14 mRNA after 24 h when normalized to beta-actin. The nuclear accumulation of [3H]-vitamin D3/receptor complexes (VDR) in a nuclear translocation assay was significantly enhanced (by 3 h) in the presence of camptothecin. We conclude that inhibition of topoisomerase I enhances vitamin D3-stimulated CD 14 expression. Topoisomerase I might either be a negatively active transcription factor itself or maintenance of DNA-bending, local supercoiling and accessibility of responsive elements might lead to reduction of VDR turnover and produce a stimulatory effect on vitamin D3-responsive transcription.
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PMID:Topoisomerase I-inhibition enhances vitamin D-responsive expression of the receptor for lipopolysaccharide binding protein CD 14. 751 Sep 56

Six heterocyclic quinones with topoisomerase I inhibiting properties and cytotoxic activities on L1210 leukemia cells were studied for their mutagenicity in four strains of Salmonella typhimurium. The tested compounds are 3-methoxyindolo[3,2-c]quinoline-1,4-diones and their derivatives in which the common pyrroloquinoline nucleus is annelated either with a benzene or a cyclohexane on a pyridine ring. Almost all quinones were found to be direct-acting mutagens at different levels in all strains, mainly TA97a and TA98. Relations were established between their structure and their mutagenic activities. The mutagenicity was found to be influenced (i) by the nature of the fourth nucleus: the pyridinic compounds were the most active, the non-aromatic ones were practically inactive; (ii) by the presence of a methyl group in the 6-position that decreased the mutagenicity. Then, the mutagenic properties were compared with the topoisomerase I inhibiting property that is one of the possible mechanisms of action for these cytotoxic quinones. The results indicated a correlation between mutagenicity and enzyme inhibiting properties.
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PMID:Structure-mutagenicity relationships in series of 11H-indolo[3,2-c]quinoline-1,4-diones, tetrahydro-11H-indolo[3,2-c]quinoline-1,4-diones and 11H-pyrido[3',4':4,5]pyrrolo[3,2-c]quinoline-1,4-diones with leukemia cytotoxic properties. Relations with topoisomerase I inhibiting properties. 752 68

Two camptothecin-resistant variants of the CEM human leukemia cell line were developed by stepwise selection in camptothecin (CPT) in vitro. The two lines, named CEM/C1 and CEM/C2, were found to be approximately 31- and 970-fold less sensitive to CPT, respectively, than the CEM parental line and variably cross-resistant to the CPT analogs 9-amino-CPT, 10,11-methylenedioxy-CPT, and topotecan. Levels of DNA-protein complex formation resulting from cell exposure to CPT were found to be progressively reduced in the CPT-resistant cells, despite equivalent CPT accumulation in the drug-sensitive and -resistant cells. Nuclear extracts (1.0 M NaCl) prepared from the CEM/C1 and CEM/C2 lines contained 1.5- to 2-fold less DNA topoisomerase I catalytic activity per microgram of protein than did extracts from the drug-sensitive CEM line, in association with altered sensitivity of the enzyme in the CEM/C1 and CEM/C2 extracts to the inhibitory activity of CPT. Only minor differences were noted in the CPT IC50s for the topoisomerase I activity in extracts from the two CPT-resistant cell lines, however, despite the marked differences in cellular sensitivity to CPT. There were notable differences in the level of CPT-induced cleavage of DNA oligonucleotides by topoisomerase I in nuclear extracts from CEM cells compared with the drug-resistant cell extracts, with very little oligonucleotide cleavage induced by enzyme in either drug-resistant cell type, despite the use of very high (100 microM) CPT concentrations. The alterations in topoisomerase I catalytic activity were associated with reduced cellular levels of both immunoreactive topoisomerase I protein (representing 59 +/- 19% [CEM/C1] and 49 +/- 12% [CEM/C2] of that in CEM, respectively) and mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Altered topoisomerase I expression in two subclones of human CEM leukemia selected for resistance to camptothecin. 757 31

(S)-10-(2,6-Dimethyl-4-pyridinyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H - pyrido[1,2,3-de][1,4]benzothiazine-6-carboxylic acid (WIN 58161) is an enantiomerically pure quinolone with outstanding bacterial topoisomerase II (DNA gyrase, EC 5.99.1.3) inhibitory and antibacterial activity. Unlike most quinolones, WIN 58161 also exhibits significant inhibitory activity against mammalian topoisomerase II (EC 5.99.1.3). DNA gyrase and topoisomerase II inhibitory activities are enantioselective. Consequently, WIN 58161 and its enantiomer (WIN 58161-2) provide useful tools to probe the contribution of topoisomerase II inhibition to the mechanism of cytotoxicity of quinolones and the potential utility of quinolone-topoisomerase II inhibitors as antitumor agents. WIN 58161 inhibited both highly purified Escherichia coli DNA gyrase and HeLa cell topoisomerase II by the promotion of enzyme-DNA covalent complexes. WIN 58161 did not bind stably to DNA via intercalation and did not enhance the formation of topoisomerase I (EC 5.99.1.2)-DNA covalent complexes. At drug concentrations that are cytotoxic to P388 murine leukemia cells, WIN 58161 promoted intracellular DNA single-strand breaks (SSBs) that exhibited the hallmarks of being mediated by topoisomerase. DNA fragments were complexed with protein, and SSBs were readily resealed at 37 degrees following drug removal. WIN 58161-2 was neither cytotoxic nor did it promote intracellular SSBs in P388. These observations suggest that the mechanism of cytotoxicity of WIN 58161 is predominantly, if not exclusively, a result of topoisomerase II inhibition. When studied in tumor-bearing mice, WIN 58161 exhibited a significant antitumor effect against each of five tumors tested, whereas neither toxicity nor antitumor activity was observed with WIN 58161-2. We conclude from these studies that WIN 58161 represents the prototype of a novel chemical class of topoisomerase II inhibitor with potential clinical utility in treating cancer.
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PMID:Mechanism of action and antitumor activity of (S)-10-(2,6-dimethyl-4-pyridinyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7 H- pyridol[1,2,3-de]-[1,4]benzothiazine-6-carboxylic acid (WIN 58161). 760 36

beta-Lapachone and certain of its derivatives directly bind and inhibit topoisomerase I (Topo I) DNA unwinding activity and form DNA-Topo I complexes, which are not resolvable by SDS-K+ assays. We show that beta-lapachone can induce apoptosis in certain cells, such as in human promyelocytic leukemia (HL-60) and human prostate cancer (DU-145, PC-3, and LNCaP) cells, as also described by Li et al. (Cancer Res., 55: 0000-0000, 1995). Characteristic 180-200-bp oligonucleosome DNA laddering and fragmented DNA-containing apoptotic cells via flow cytometry and morphological examinations were observed in 4 h in HL-60 cells after a 4-h, > or = 0.5 microM beta-lapachone exposure. HL-60 cells treated with camptothecin or topotecan resulted in greater apoptotic DNA laddering and apoptotic cell populations than comparable equitoxic concentrations of beta-lapachone, although beta-lapachone was a more effective Topo I inhibitor. beta-Lapachone treatment (4 h, 1-5 microM) resulted in a block at G0/G1, with decreases in S and G2/M phases and increases in apoptotic cell populations over time in HL-60 and three separate human prostate cancer (DU-145, PC-3, and LNCaP) cells. Similar treatments with topotecan or camptothecin (4 h, 1-5 microM) resulted in blockage of cells in S and apoptosis. Thus, beta-lapachone causes a block in G0/G1 of the cell cycle and induces apoptosis in cells before, or at early times during, DNA synthesis. These events are p53 independent, since PC-3 and HL-60 cells are null cells, LNCaP are wild-type, and DU-145 contain mutant p53, yet all undergo apoptosis after beta-lapachone treatment. Interestingly, beta-lapachone treatment of p53 wild type-containing prostate cancer cells (i.e., LNCaP) did not result in the induction of nuclear levels of p53 protein, as did camptothecin-treated cells. Like other Topo I inhibitors, beta-lapachone may induce apoptosis by locking Topo I onto DNA, blocking replication fork movement, and inducing apoptosis in a p53-independent fashion. beta-Lapachone and its derivatives, as well as other Topo I inhibitors, have potential clinical utility alone against human leukemia and prostate cancers.
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PMID:Beta-lapachone-mediated apoptosis in human promyelocytic leukemia (HL-60) and human prostate cancer cells: a p53-independent response. 764 Nov 80

Topotecan [(S)-9-dimethylaminomethyl-10-hydroxycamptothecin hydrochloride; SK&F 104864-A, NSC 609699], a water soluble semisynthetic analogue of the alkaloid camptothecin, is a potent topoisomerase I inhibitor. Here we show that topotecan stabilizes topoisomerase I/DNA cleavable complexes in radiation-resistant human B-lineage acute lymphoblastic leukemia (ALL) cells, causes rapid apoptotic cell death despite high-level expression of bcl-2 protein, and inhibits ALL cell in vitro clonogenic growth in a dose-dependent fashion. Furthermore, topotecan elicited potent antileukemic activity in three different severe combined immunodeficiency (SCID) mouse models of human poor prognosis ALL and markedly improved event-free survival of SCID mice challenged with otherwise fatal doses of human leukemia cells at systemic drug exposure levels that can be easily achieved in children with leukemia.
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PMID:In vitro and in vivo activity of topotecan against human B-lineage acute lymphoblastic leukemia cells. 774 43

Fluorescence digital imaging microscopy (FDIM) has been used to perform a cell cycle analysis of both the amount and the distribution of nuclear DNA topoisomerase I in individual CEM human leukemia cells. Cells were stained by indirect immunofluorescence methods using a polyclonal antiserum generated with a 21-amino-acid peptide representing amino acids 219-239 of human topoisomerase I. Immunohistochemical staining was followed by staining with Hoechst dye 33342, allowing DNA content to be determined in each cell. Cell cycle analysis showed that nuclear topoisomerase I content doubled (2.2-fold increase) as the cells progressed from G1 to G2/M phases of the cell cycle. However, when normalized for nuclear size, topoisomerase I content per nuclear area remained almost constant (1.3-fold increase). For comparison, we measured the amount of proliferating cell nuclear antigen (PCNA), a protein whose expression fluctuates during the cell cycle. Nuclear PCNA content increased 2.7-fold from G1 to S phase, then declined in G2/M- phases, whereas PCNA content per nuclear area increased 1.7-fold from G1 to S phase. We also measured topoisomerase I content in leucine-deprived cells to determine if altered growth conditions affect topoisomerase I protein expression. Compared to CEM cells in logarithmic growth, leucine-deprived CEM cells had 1.8-fold less topoisomerase I content per nuclear area. Subnuclear distribution studies of proliferating CEM cells showed topoisomerase I to be localized predominantly in the nucleoli throughout the cell cycle. In contrast, leucine-deprived cells exhibited a perinuclear distribution of topoisomerase I. Our results show that FDIM is a useful technique in determining the cell cycle position and both the content and the distribution of topoisomerase I as well as other nuclear proteins in individual cells.
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PMID:Cell cycle analysis of amount and distribution of nuclear DNA topoisomerase I as determined by fluorescence digital imaging microscopy. 774 94

Changes in topoisomerase I (topo I) levels and localization were examined during the course of granulocytic maturation in vitro and in vivo. Western blotting revealed that granulocytic maturation in DMSO-treated HL-60 human leukemia cells was accompanied by a 5-fold decrease in topo I polypeptide content. Consistent with this result, 3- to 5-fold higher concentrations of the topo I poison camptothecin were required to stabilize topo I-DNA adducts in DMSO-treated HL-60 cells compared to untreated cells. Northern blotting revealed that these changes occurred without any decrease in topo I message. Immunolocalization studies revealed that these quantitative changes were accompanied by redistribution of topo I away from the nucleoli, where it was prominently accumulated in untreated HL-60 cells, to a more uniform nuclear distribution in DMSO-treated cells. Similar changes occurred during granulocytic maturation in human marrow in vivo. Western blotting revealed that topo I levels in normal progranulocytes were 50% as high as those in HL-60 cells, levels in metamyelocytes were 35% as high as HL-60 cells, and levels in peripheral blood granulocytes were 5% as high as HL-60 cells. Two other polypeptides that are concentrated in nucleoli, poly(ADP-ribose) polymerase and B23/nucleophosmin, also decreased during the course of granulocytic maturation. These changes were accompanied by an alteration in topo I localization similar to that observed in HL-60 cells during the course of granulocytic maturation. Conversely, treatment of human lymphocytes with the mitogenic lectin concanavalin A resulted in a 3-fold increase in topo I polypeptide content concomitant with a prominent increase in the amount of nucleolar antigen. These observations not only provide a context for understanding the recent observation that topo I levels are higher in human leukemia specimens than in normal marrow but also raise the possibility that elevated topo I levels in other cells might reflect alterations in nucleolar structure and function.
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PMID:Changes in topoisomerase I levels and localization during myeloid maturation in vitro and in vivo. 788 18


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